Certain x-acyl



CERTAIN 4-ACYL, 1-(p-HYDR0XYPHENYL)-2-. Pl-IE NYL, asnroxorvmzounmus No Drawing. Application December 12, 1955 Serial No. 552,290

. Claims priority, application switaerland December 16, 1954 e .3 Claims. (Cl. 260-310) 2,927,921. Patented Mar. 8, 1960 ICC hydride, but also acid halides can react in the desired manner, also in the absence of condensingagents, on

heating with compounds of the general Formula Ill.

The present invention concerns 4-substituted 1.2-diphenyl-3.5 dioxo-pyrazolidines which can be used thera pcutically as well'as processes for the production thereof. '1.2 diphenyl-3.5-dioxo-4-n-butyl-pyrazolidine has al- 1 ready attained great therapeutical importance as a prepa- Howration for the treatment of rheumatic complaints. ever, 1.2-diphenyl-3.S-dioxo-pyrazolidines substiuted in the 4-position by an acyl radical have not been known up to now.

Surprisingly it has now been foundthat such compounds of the general formula:

' CO-NAr| R-oo-c OO-N-An I I or the tautomeric forms thereof wherein:

general formula:

R-COOI-l II or the free carboxylic acid with a malonyl hydrazobenzene, (=l.2-diphenyl-3.S-dioxo-pyrazolidine) of the general formula:

CO-NAri c O-NAr1 III the reaction being performed if necessary in the presence of a condensing agent.

The compounds produced according to the present invention have valuable therapeutical properties, in particular antiphlogistic and antipyretic activity. A particularly advantageous modification of the process for their production is the condensation of a carboxylic acid halide or anhydride with a compound of the general Formula III in the presence of pyridine or another tertiary organic base, and also in the presence of inorganic basic condensation agents such as, for example, potassium carbonate. Carboxylic acid halides can also be reacted in the presence of aluminium chloride analogous to the condensation of carboxylic acid chlorides with 1-phenyl-2.3-dimethyl-S-pyrazolone described by B. Zorn and F. H. Schmidt in the Zeitschrift fiir physiolog. Chemie, 298, 140 (1954). Examples of condenration agents with a similar action are ferric chloride and bortrifluoride. Further, also carboxylic acid esters can be used in the presence of alkali metal alcoholates for the reaction with compounds of the general Formula III. In particular acid anyhdrides such as, e.g. acetan- Whilst the addition of a solvent is often superfluous on using acid .anhydrides, the reactions with acid halides are advantageously performed in inert organic solvents; when basic substances are used as condensing agents, eg. in benzene or chloroform and-when using aluminium chloride as condensing agent, for example carbon tetrachloride, chloroform or nitrobenzene." Reactions with carboxylic acid esters can be performed for example in alcohols having a suitableboiling point or also in inert organic solvents. 1 p

" 3 Compounds of the general Formula I in which Ar and also, possibly Ar have a hydroxyl group can, like compounds substituted differently, be produced by condensation of the corresponding starting material, here of l-hy- C O-N-Ara IV wherein:

Ar' represents an aralkyloxyphenyl radical and Ar has the meaning given above, here in particular that of an unsubstituted phenyl radical or of an aralkyb oxyphenyl radical,

and hydrogenolysing the condensation product by means of catalytically activated hydrogen. In particular the benzyloxyphenyl radicals are named as suitable aralkyloxyphenyl radicals Ar' and, possibly, Ar which radicals are split in the hydrogenolysis into hydroxyphenyl radicals and toluene. As condensing agents, those named above, in particular pyridine, can be used.

Further, compounds of the general Formula I in which Ar and possibly also Ar have a hydroxyl group,

can also be obtained by hydrolysis of compounds in which Ar or Ar and Ar, are substituted by one or more radicals of the formula R-COO.

The new 1-(p-hydroxypheny1-2-phenyl-3.5-dioxo-4- acyl-pyrazolidines are mostly colourless crystallised compounds. They form salts, some of which are diificultly soluble, with inorganic and organic bases.

The following examples serve to further illustrate the invention. Parts are given as parts by weight and theirrelationship to parts by volume is as that of grammes to cubic centimetres. The temperatures .are in degrees centigrade.

Example 1 14.1 parts of benzoyl chloride are dissolved in 15 parts by volume of benzene and added dropwise while stirring to a suspension of 35.8 parts of p-benzyloxy malonyl hydrazobenzene (produced from p-benzyloxy hydraubcnzene and malonic acid diethyl ester, M.P. -190 on decomposition), 250 parts by volume of benzene and 35 parts by volume of pyridine. On completion of the reaction, the product is filtered under suction, and the precipitate is recrystallised from alcohol, M.P. 116-117.

23.1 parts of the l-(p-benzyloxy-phenyl)-2-phenyl-4- benzoyl-3.S-dioxo-pyrazolidine.so obtained are dissolved in 400 parts by. volume of 1 N-caustic soda lye and 800 parts by volume of alcohol, and, at room temperature and normal pressure, are shaken with 20parts of nickel Such compounds can.

3 1 t catalyst '(Raney nickel) in an H atmosphere. After taking up the calculated amount of hydro-gen (1 mol per mol starting product) practically no more hydrogen is taken up. The catalyst is filtered off and 250 .parts by volume of 2 N-hydro'chloricacid and 100 parts by volume of water are added under ice cooling to the filtrate. On completion of the crystallisation, the crystallised product l-(p-hydroxyphenyl)-2-phenyl-4-benzoyl- 3.5-dioxo pyrazolidine is recrystallised from 80% alcohol. It melts at 198-200. s

For example, also l-(p-benz'yloxy-phenyl)-2-phenyl 4- phenyl-accty1-3.5dioXo-pyrazolidine (M.P. 103-106") and l-(p-hydroxyphenyl)-2-phenyl 4-phenylacetyl-3.S-dioxo-pyrazolidine (ll/LP. 155-157") are obtained in an analogous manner. 7

Example 2 13.4 parts'of p-hydroxy malonyl hydrazobenzene (produced from p-benzyloxy malonyl hydrazobenzene by hydrogenolysis analogous to the process of Example 1, MP. l75-185) are suspended in 100 ,parts by volume ofbenzene and 17 parts by volume of pyridine whereupon 5.4 parts of butyryl chloride dissolved in parts by volume of benzene are added dropwise while stirring.

The reaction mixture is stirredfor about 14 hours at room temperature and then the precipitate is filteredoif under suction and stirred up and extracted with 500 parts by volume of 2 N-sodium carbonate solution. The sodium carbon-ate extract is filtered with charcoal and then acidified with 2 N-hydrochloric acid under ice cooling. The precipitate which forms is filtered off under suction and recrystallised from aqueous alcohol. The l- (p-hydroxy phenyl)-2-phenyl-4-butyryl-3.S-dioxo-pyrazolidine melts at 144146.

What we claim is: a

1. l-(p-hydroxyphenyl)-2-pheny1-4-butyryl-3.$ dioxopyrazolidine.

2. 1-(p-hydroxyphenyl)-2-phenyl 4 phenylacetyl-3.$- dioxo-pyrazolidine.

3. l-(p-hydroxyphenyl) 2 phcnyl-4-benzyl-3.5-dioxopyrazolidine.

References Cited in the file of this patent Hafliger Jan. 25, 1955 

1. 1-(P-PHYDROXYPHENYL)-2-PHENYL-4-BUTYRYL-3,5-DIOXOPYRAZOLIDINE.
 2. 1-(P-HYDROXYPHENYL)-2-PHENYL-4-PHENYLACETYL-3,5DIOXO-PYRAZOLIDINE.
 3. 1-(P-HYDROXYPHENYL)-2-PHENYL-4-BENZYL-3.5-DIOXOPYRAZOLIDINE. 